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Therapeutic Plasma Exchange:
principles and practice in
pediatric nephrology
Peyman Eshghi MD.
Prof. of Hematology&Oncology
Pediatric Congenital Hematologic Disorder Research Center
Mofid Children Hospital –SBMU
1394
References
1) Kim, H. “Therapeutic Pediatric Apheresis.” Journal of Clinical Apheresis 15 (2000):129-157
2) Chan, K.W., and M. Bond. Practical Considerations of Apheresis in Peripheral Blood Stem Cell Transplantation. Lakewood: COBE Laboratories Inc. 1994
3) Jeter, E.K., and R.L. Rogers. Apheresis: Principles and Practice. Bethesda: AABB 1997
4) Gorlin, J.B. “Pediatric Large Volume Peripheral Blood Progenitor Cell Collections From Patients Under 25 kg: A Primer.” Journal of Clinical Apheresis 11(1996):195-203
5) Demeocq F. “Successful blood stem cell collection and transplant in children weighing less than 25 kg.” Bone Marrow Transplantation 13 (1994):43-50
6) Woloskie S. “Leukodepletion for Acute Lymphocytic leukemia in a Three-Week-Old Infant.” Journal of Clinical Apheresis 16:31-32 (2001)
7) Stefanutti. Therapeutic apheresis in low weight patients:technical feasibility, tolerance, compliance, and risks, Transfusion and Apheresis Science 31 (2004) 3–10
8) Plasmapheresis;principles ,Methods and Clinical use. www.ibto.ir
9) Joseph Schwartz ,et al. Guidelines on the Use of Therapeutic Apheresis in Clinical
Practice. Journal of Clinical Apheresis 28:145–284 (2013)
Apheresis:Definition & History ;Principles
and practice
TPE: key points
Pediatric considerations
TPE in Pediatric Nephrology Diseases
Apheresis:
Definition & History
Definitions
Apheresis : [ in Greek] “to carry away”
Cytapheresis;Plateletphresis;Plasmapheresis
Plasmapheresis: plasma is removed and replaced
w/plasma substitute (N.S. and/or 5% albumin)
Plasma exchange: plasma is removed and
exchanged w/allogeneic plasma
TPE: therapeutic plasma exchange
Use of Apheresis
Collection
– facilitate collection of a blood component (plt, wbc) from an
allogeneic donor
– collection of hematopoietic progenitor cells
Therapy (therapeutic apheresis):
– removing undesired substances like antibodies, lipids from the
circulation,which are :
• present in plasma
• tightly bound to plasma proteins
– reducing excess wbc/plt in pts w/myeloproliferative disorders
– automated exchange of sickled rbc
Abnormal Substances Removed From
the Circulation by TPE
1)Paraproteins (Waldenstorm’s Macroglobulinemia)
2)Autoantibodies (Myasthenia Gravis, Goodpasture’s
syn.)
3)Lipids (LDL in familial hypercholesterolemia;
phynatic acid in refsum’s disease
4)Toxins or drugs (that are bound to albumin)
5)Circulating immune complexes (CIC)
6)Soluble mediators of inflammatory response
(activated complement component, vasoactive
substances)
History:
Plasmapheresis (removal of plasma with return of RBC) first
performed 1914 John Abel at Johns Hopkins University in a
dog in context of artificial kidney research
1959 Skoog and Adams used manual plasmapheresis in
patient with Waldenstrom’s to reduce serum viscosity
Developed manual plasmapheresis was Major method of
collecting source plasma from paid donors until early 1980’s
History Earliest work in early 1950’s by Dr. Edwin Cohn at Harvard
– Devised fractionation scheme for plasma and important in providing
albumin for WWII
– Blood into conical centrifugal separation chamber
1962 IBM engineer son dx with CML
– Together with Dr. Emil Freireich and IBM developed NCI-IBM (2990) at National Cancer Institute
– Initially process 11L of blood from CML patients for leukopheresis
1964 studies on CLL patient leukopheresis
1969 1st automated plasma exchange procedures
Apheresis:
Principles of Separation& Methods
Centrifugal separation based on special gravity
Plasma (1.025-1.029 specific
gravity)
Platelet (1.040)
Mononuclear (lymph, mono,
PBSC,blast) (1.070)
Granulocyte (neut, baso, eos)
(1.087)
Neocyte RBC
RBC (1.093-1.096)
METHODS
1)Centrifugation
A- manual:
B-automatic: – Intermitent Flow Centrifugation [IFC]
– Continious Flow Centrifugation [CFC]
2)Filtration: based on size ,not gravity
Smaller; less EV
3)Combined Centrifugation &Filtration
4)Afinity Adsorption Apheresis : based on physical,Chemical or Immunological properties
Manual
vs Automatic :
Cheaper& Simpler
No machine
Less dependent to
size of IV access
Less volume/slow
Error in RBC return
Alternative to
automatic method
Intermitent Flow Centrifugation [IFC]:
Intermittent flow – Blood processed in
discrete batches
– Separation until container filled with dense component (RBC)
– Needs to empty before next batch
Haemonetics MSC plus, V50,V30
Continious Flow Centrifugation [CFC]
– All fractions can be removed in ongoing manner • Do not need to empty container until end of
procedure Cobe spectra, CS 3000, Fresnius AS 104
Intermittent vs. Continuous Flow
Intermittent flow: procedure performed in cycles
(withdrawal, separate, re-infuse). – Pro: Smaller machine; one needle access for peripheral access
– Con: extracorporeal volume (ECV) can be high (bad in kids and
the elderly with low total blood volume or TBV), fluctuations in
hemodynamics
– E.g: Haemonetic V50
Continuous flow: blood withdrawn, processed
and reinfused simultaneously – Pro: smaller ECV, hemodynamic stability, faster
– Con: 2 venipuncture sites for peripheral access
– Examples: COBE Spectra, Fenwal C3000 Plus, Fresenius AS
104
Membrane Filtration
Conceptually similar to
hemodialysis
Use limited to plasma
exchange
Blood is pumped to the filter
membrane
Membranes with pore sizes
that can trap high MW
proteins, exclude cellular
elements
Cellular components
combined with replacement
fluid, returned to patient
Membrane Filtration (MF) vs. Centrifugation
Similar efficiency and safety
Membrane filtration (MF) is faster: because time
is required to set up a centrifugal interface
Different anticoagulants:
Membrane filtration: heparin
Centrifugation: usually citrate
MF cannot remove cellular elements, therefore
use is limited to plasma exchange
MF widely used in other areas of the world:
Japan, Europe. Uncommon in the US
immunoadsorption
In contrast to conventional plasma-
exchange therapy, immunoadsorption
removes harmful agents while retaining
natural plasma components, enabling the
patient’s own modified plasma to be used
as a replacement solution.
Perfuse plasma through a selective removal
column/filter
– Dextran sulfate column: removes LDL
– Staphylococcal protein A: removes IgG by binding to
the Fc portion
immunoadsorption
Maximum rate of 50ml/min
2.5 -3 plasma volume are proccessed in each session
Treatment period#2 days , allowing overnight equilibrium
The same columns can be kept refrigerated (in0.1% Thiomersal) and used again for same patient
TPE :
key points
Main Questions about TPE
Characteristics of pathogen for uptake
Expectation for success
Plasma Volume for Exchange in each
session
TPE intervals
Fluid substitutions
TPE and interactions
Lab tests needed before and during TPE
Where and by Whom it should be done
Characteristics of pathogen for the most
efficient uptake
Macromolecules(>15000 D)
Long half life : IgG with21 days hl
Slow synthesis rate
Intravascular compartment
Toxic OR refractory to conventional less
complicated treatments
Expectation for success
The correlation will be
correct If pathogen is: – totally intravascular ;
– not produced ;
– not consumped.
Accordingly the success rate
could be sorted descendingly:
1. Fibrinogen ,C3
2. IgM,Cholestrol,ALP
3. IgA,IgG,LDH,CK
4. Small molecules & minerals
Little advantage beyond 1.0-
1.5 volumes:
– Decrease efficiency: • 1pv= 63%,
• 2 pv=86% ,
• 3 pv=95%
– More time (2Hr for each PV)
– More cost
Removal of IgG and IgM by plasma exchange:
IgG IgM
Intravascular amount 45% 76%
“total body”removal
1 PV Ex. 28% 48%
1.5 PV Ex. 35% 59%
2 PV Ex. 39% 65%
Rebound effect & Neg Feedback: less IgG level leads to more synthesis
Immunosuppresive treatment has agonistic effect on TPE
IVIG blocks FcRn :more free Intravascular pathogen IgG ;more
pathogen IgG catabolism and more pathogen IgG available for
TPE
TPE is more efficient for natural IgG than Paraprotein IgG(due
to more plasma volume )
TPE intervals & sessions
Depends on:
– Type of pathogen particle
– Severity of disease & clinical status
– Regeneration of pathogen
– Redistribution of pathogen
– Adjuvant Rx: Immunosuppresive Rx ; IVIG
TPE intervals & sessions
GBS: continue 1-2
times/W untill clinical
improvement
TTP: daily untill clinical
improvement:
normalization of LDH and
Platelet level for at least
2-3 days
GPS: daily for at least 2
weeks
Combination with immune
suppresives:continue for
5-10 times untill drug
response expectation
Fluid substitutions
Replacement
solutions
Advantages Disadvantages Indication
Crystalloids • Low cost
• Hypoallergic
• No viral risk
• Rapid exit to EVC: 2-3
volumes required
• No Coaglation
• No Immunoglobulins
• <500-1000 cc TPE
• Hyper viscosity
Albumin 5% • Iso/mild hyper-oncotic
• No inflammatory
mediators
• No viral risk
• High cost
• No Coaglation
• No Immunoglobulins
• Dilutional anemia
• Drug cross reaction:
ACEI
• Rare reactions due to
pre-kalicrein and
pyrogens
Plasma:
FFP
CPP
SDT-plasma
QR-Plasma
• Low cost
• Maintain levels of:
• Immunoglobulins
• Complements
• Antithrombin
• proteins
• Viral transmission risk
• ABO compatibility test
• Allergic reaction
• TRALI
• Sensitization
• Citrate load
• First choice in:
•TTP
•Repeated TPE
•Bleeding tendency
•Liver failure
•Cryo-poor plasma is
indicated for TTP
refractory to TPE with
plasma
Hydroxyethyl
starch
• Moderate cost
• Isotonic
• No inflammatory
mediators
• No Coaglation
• No Immunoglobulins
• Long-term residual of
HES
• Contraindicated in
renal failure
• Indicated in patients with
sever reactions to
albumin and plasma
Recommended method
Due to Hypo-oncotic characteristic of crystalloids
which may lead to intravascular fluid deficit,usually
used in combination with albumin: start procedure
with NS replacement, then finish with albumin
repalcemen
Albumin 4-4.5% (Albumin5% 60-70% + N/S 30-
40%)
TTP: FFP or CPP 60-70% +20-30% N/S
Repeated TPE(prevention of coagulopathies): last
cycle of each session 10-15 cc/kg FFP
Patient History and Medications
Does patient have a disease which is
amenable to treatment by the requested
apheresis procedure
Does the patient/donor capable of sustaining
the fluid shifts associated with apheresis
Certain medications, most notably
antibiotics and anticoagulant can be
removed by apheresis -should be given
immediately afterthe procedure
Angiotensin-converting enzymes (ACE)
inhibitors
TPE and interactions:
Drug clearance
No change needed:
Digixin;prednisolone;propranolol;valporic acid;
phenobarbital;cyclosporine;ceftriaxone;ceftazidim
Added dose needed:
Salycilates;aminoglycosides;phenytoin(?)
Should be omitted immediately after TPE( partial
enzyme deficiency)
– Choline esterase: neuromuscular blocking drugs
(succinylcholine)
– Catabolic Enzymes for bradykinins :ACEI(captopril,enalapril)
Normal Constituents Removed
Coagulation factors:
– Most coagulation factors are lost at the same rate
– Rapidly synthesized;replacement usually is 2-3 days
following exchange (VIII;X; VWF:RCO after4 h)
– Practical: measure PT/PTT/Fibrinogen every 2-3 days
(rather then daily)
Platelets:
– 25-30% per procedure
– Endogenous synthesis replaces lost platelets within 2-4
days (except hypoplastic/aplastic marrow)
Lab work(esp. chemistry): not immediate post-
procedure; allow equilibrium intra/ extravascular
space
Routine supplementation with FFP not necessary
for most patients
Fibrinogen replaced most slowly (but this is variable
depending on patient –Fg is an acute phase
reactant, elevated in many patients
If consecutive TPE’s with albumin replacement are
performed, check fibrinogen. If falls <100mg/dL,
consider increasing interval between exchanges, or
supplement with FFP/cryoprecipitate
Lab tests needed before and during TPE
Pathogen particle or element
CBC:Hct; Platelet
PT;PTT
Electrolyte
Serum Albumin & Globulin
Some hours after session or just before the
next session
Site & persones
Expert persons: Nurse and physician
CPR and Cardiac monitoring and assist
set
In sever cases, and frequent,high volume
TPE :in hospitals with ICU
Pediatric Apheresis - Considerations
How Small Is Too Small?
Vascular Access
TBV Calculation
Blood Prime
Anticoagulation
Pump Flow Rates
Collect Flow Rates
Volumes Processed
Adverse Effects
Background
The use of therapeutic apheresis in paediatric patients is still very limited:
technical difficulties :
– The choice of a suitable machine and method;
– The choice of suitable vascular access andthe insertion site (jugular vein, subclavian vein, femoral vein),
– and the type of central venous catheter to be used (tunnelling, percutaneous, long-term, short-term)
psychological aspects(Admission to hospital, extracorporeal treatment
physiological response/ standards : – Greater difficulty in metabolising citrates
– Blood volume vs ECV
Pediatric Apheresis - Considerations
Adverse Effects
Pediatric Apheresis - Considerations
Adverse Effects
Citrate toxicity
Hypotension/Vasovagal
Access related complications
– Infection
– Hematoma
– Pneumothorax
– Air emboli
– etc
Platelet loss
Hemoglobin level drop
Hypofibrinogenemia
Transfusion reactions
Allergic reactions
– paediatric patients are particularly subject to the toxicity of citrates, they have greater difficulty in metabolising citrates in critical situations
– Symptoms of citrate toxicity are nonspecific and can be difficult to detect in young children: Abdominal pain, vomiting, pallor, brady-, tachycardia, hypotension, anxiety, sweating, agitation, licking their lips (tingling)…
– In infants and critically ill, semi-conscious patients, hypotension may be the first sign of hypocalcemia
Pediatric Apheresis - Considerations
Adverse Effects - Hypocalcemia
Pediatric Apheresis - Considerations
Adverse Effects - Hypocalcemia
Magnesium levels
Serum protein levels
Decreased serum glucose levels
Drop rate of ionized calcium
Differences in patient sensitivity to lower calcium levels may be due, in part, to differences in:
Pediatric Apheresis - Considerations
Adverse Effects - Hypocalcemia
In small children, obtain an ionized calcium level before and during the
treatment
High volume(>1-2V)frequent &repeated TPE: Check Serum Ca hours
after session or just before the next session
Supplement calcium
Limit the amount of citrate delivered to 1 - 1.5 mg/kg/min2
Wash RBCs used for priming
Avoid transfusions on the same day
Use a blood warmer
heparin or ACD associated heparin may be used as an
anticoagulant,(In the absence of any clotting disorders)
Strategies to prevent Hypocalcemia
according to the literature:
Pediatric Apheresis - Considerations
Adverse Effects - Hypocalcemia
Bolus dosing of calcium gluconate 0.5 g/10 kg
at 1. and 2. hour of collection5 OR Calcium gluconate 10% 10cc+1000 cc N/S as replacement solution
Infusion from different vein
Simultaneous reinfusion of calcium solution into the return line just before it reenters the patient1
Older patients with vague symptoms can be treated with oral calcium carbonate, 10 mg/kg2
Calcium-Supplementation Options
according to the literature:
Pediatric Apheresis - Considerations
Adverse Effects – allergy & anaphylaxis
Plasma proteins(IgA,complements,etc.)
HES:Alternative complement activation(C3a&C5a)
Ethylen Oxide in plasmapheresis tube set: hapten
formation
ACEI medicines:no inactivation of bradykinin by
kininase I&II
– Plasmapheresis tube sets and patient`s plasma
– Rapid Albumin infusion increase pre-kalikrein and consequently
bradykinin
(ACEI should be discontinued 48 h before TPE)
Pediatric Apheresis - Considerations
Adverse Effects - Hypotension
Decreased Intravascular Volume: – High extracorpular Volume(>10.5 cc/kg)
– Clinical condition: neurologic disorders; severely sick patients ,etc
– Intermittent method of TPE
– Fluid shift: • When blood is removed in the beginning of a procedure
• Cristaloid replacement
– Negative Fluid balance: • Anticoagulant+Replacement Fluid < Plasma Removed
Vasovagal reflex
To minimize the risk of hypovolemia and fluid shift:
Limit the patients extracorporeal (ECV) to <15% of
patients TBV at all times:
– ECV: the “dead spaces” (tubing, chambers) of an instrument.
(Range 150-500ml) that need to filled to complete the apheresis
circuit
Priming the instrument with colloid solution or RBCs
(washed RBCs diluted with 5% albumin ) may be
necessary for a pediatric/small pt
Hct during TPE should be > or = 24%
Start at a slow inlet flow rate of 10 ml/min, then increase flow rate in increments of 5 ml/min2
Pediatric Apheresis - Considerations
Adverse Effects – catheter complications
Infection
Thrombosis
Nerve insults
Hematoma and bleeding
AV fistula
Air emboli(acute dyspnea,
cyanosis,tachycardiaand hypotension)
Pediatric Apheresis - Considerations
Adverse Effects – hypokalemia
Albumin: 35% dilutional decrease in
serum potasium
Aphresis Indication Categories (ASFA/AABB)
Category I: First line therapy –proven to be effective
Category II: Adjunct therapy –proven to be beneficial in
some instances
Category III: May be-evidence is conflicting but there is
some suggestion of benefit, can be considered if
conventional therapy is failing
Category IV: Disorders in which published evidence
demonstrates or suggests apheresis to be ineffective or
harmful.IRB approval is desirable if apheresis treatment
is undertaken in these circumstances.
Category P: Pending
Rationale for therapeutic apheresis:
– TPE can effectively remove the autoantibody or mutated circulating
complement regulators while replacing absent or defective complement
regulators
– TPE over PLx: benefits without risk of volume overload, development of
hyperproteinemia, or refractoriness to regular plasma infusion
Duration and discontinuation/number of procedures:
– no standardized approach : based upon patient response and condition
– vascular access, RBC prime, and calcium supplementation are of special concern.
– 5 times per week for 2 weeks, then 3 times per week for 2 weeks with outcome
evaluated at day 33 (Sanchez)
– neither continued treatment after initial therapy failure nor ongoing prophylactic
treatment for patients with remission
THROMBOTIC THROMBOCYTOPENIC PURPURA
Duration and discontinuation/number of procedures:
TPE is generally performed daily until the platelet count is above
150 ×109/L, and LDH is near normal for 2 to 3 consecutive days.
The median number of TPE procedures to establish hematologic recovery
is 7–8 days.
The role of tapering TPE over longer duration has not been s tudied
prospectively but is used frequently. Persistence of schistocytes alone on peripheral blood smear, in the
absence of other clinical features of TTP, does not preclude
discontinuation of treatment.
plasma ADAMTS13 protease levels are not
severely deficient nor are ADAMTS13 inhibitors
detectable in patients with TATMA. Therefore, a
therapeutic rationale is undefined and
consistent with the uncertain clinical efficacy.
Pediatric Apheresis - Considerations
Any Questions?
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